tbuckley/cabot-search huggingface dataset:
Abstract P3074: Immune Checkpoint Inhibition Reshapes Cardiac Immune Landscape Through Crosstalk Between Macrophage And T-cell
Authors: Pan Ma, Jing Liu, Lulu Lai, Juan Qin, Debbie Sultan, Andrea Bredemeyer, Geetika Bajpai, Guoshuai Feng, Junedh Amrute, Inessa Lokshina, Yongjian Liu, Chieh-Yu Lin, Javid Moslehi, Kory Lavine
Journal: Circulation Research (2022)

Immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed cell death protein 1(PD-1)/ programmed death-ligand 1(PD-L1) have revolutionized cancer management since the approval. However, they are associated with immune-related adverse events (irAEs), including myocarditis. ICI-associated myocarditis is often fulminant and fatal. The associated major risk factor is the combination of CTLA-4 and PD-1 inhibition. The mechanistic basis of ICI-associated myocarditis is unclear and mechanism-based treatment strategies are needed. Crosstalk between T-cells and macrophages may represent one pathogenic mechanism underlying ICI-associated myocarditis. We employed an established mouse model Ctla4 +/- Pdcd1 -/- to study the crosstalk between T-cells and macrophage in the heart and its impact on reshaping cardiac immune landscape using unbiased single cell-RNA-seq technology. We discovered a more inflammatory cardiac microenvironment in ICI-associated myocarditis mouse, characterized by CD68 + cells infiltration, robust CCR2 signal, enhanced T-cells activation with interferon gamma (IFN-γ) secretion and increased frequency of Cxcl9 + Cxcl10 + macrophages with an activated phenotype enriched in response to IFN-γ. Importantly, the existence of Cxcl9 + Cxcl10 + macrophages (characterized by CD16α and CXCL9/CXCL10 expression) was confirmed in human ICI-associated myocarditis specimens which establishes a connection between mouse model and human disease. Analysis of cell communication between myeloid cells and T-cells predicted that Cxcl9 + Cxcl10 + macrophages communicate with T-cells via IFN-γ-IFN-γR and Cxcl9/Cxcl10-CXCR3 signals. Pseudotime time analysis suggests Cxcl9 + Cxcl10 + macrophages were derived from monocytes. Blocking IFN-γ signal prolonged the survival time of ICI-associated myocarditis mouse and reduced emergence of Cxcl9 + Cxcl10 + macrophages in the heart suggesting specific blocking the mediator of crosstalk between T-cells and macrophages attenuated ICI-associated myocarditis. This study will provide support to the usage of IFN-γ as a potential target to prevent ICI associated myocarditis during or at the end of ICI therapy in cancer patients.
The air we breathe
Authors: GW Sybrecht
Journal: European Respiratory Journal (1988)

<b>Introduction.</b> The Organ Care System (OCS) is a sophisticated platform to preserve, evaluate and recondition donated lungs for transplantation (LTx). The impact of OCS on inflammatory response is not known. Here we focus on leukocyte responses and release of neutrophil-derived permeability and oxidative stress mediators. <b>Methods.</b> Neutrophil kinetics were retrospectively evaluated in 269 patients receiving standard-LTx (n=248) or OCS-LTx (n=21) between 2010 and 2015. In a subset of 40 patients, plasma levels of Myeloperoxidase (MPO) and Heparin Binding Protein (HBP) were measured by ELISA at baseline and at 0, 6, 12, 24, 48, and 72 hours. <b>Results.</b> Total leukocyte and neutrophil counts and CRP levels were significantly lower in the OCS group on day 1 and 2. Figure 1 shows plasma levels of HBP and MPO demonstrating lower mediator release at several time points in the OCS group. Postoperative gas exchange, duration of ventilation, ITU and hospital stay were similar between groups. Patient with severe grade3 Primary Graft Dysfunction (PGD) had higher HBP at T0 after LTx compared to patients with no PGD (p= 0.038). <b>Conclusions.</b> Recipients of OCS lungs exhibit lower leucocytosis and neutrophilia and lesser inflammatory mediator release with similar clinical outcomes compared to standard LTx. PGD is associated with increased HBP release suggesting HBP as a potential biomarker of lung injury.
Hiccup in adults: an overview
Authors: S Launois, JL Bizec, WA Whitelaw, J Cabane, JP Derenne
Journal: European Respiratory Journal (1993)

Hiccup is a forceful, involuntary inspiration commonly experienced by fetuses, children and adults. Its purpose is unknown and its pathophysiology still poorly understood. Short hiccup bouts are mostly associated with gastric distention or alcohol intake, resolve spontaneously or with simple folk remedies and do not require medical attention. In contrast, prolonged hiccup is a rare but disabling condition which can induce depression, weight loss and sleep deprivation. A wide variety of pathological conditions can cause chronic hiccup: myocardial infarction, brain tumour, renal failure, prostate cancer, abdominal surgery etc. Detailed medical history and physical examinations will often guide diagnostic investigations (abdominal ultrasound, chest or brain CT scan...). Gastric and duodenal ulcers, gastritis, oesophageal reflux and oesophagitis are commonly observed in chronic hiccup patients and upper gastrointestinal investigations (endoscopy, pH monitoring and manometry) should be included in the diagnostic evaluation systematically. Etiological treatment is not always available and chronic hiccup treatment has classically relied on metoclopramide and chlorpromazine. Recently, baclofen (LIORESAL) has emerged as a safe and often effective treatment.
Abstract P3120: Cardio And Neurotoxicity Of Repurposed Anti-COVID-19 Drugs
Authors: Martin Nicholson, Ching-Ying Huang, Jyun-Yuan Wang, Ting Chien-Yu, Yu-Che Cheng, Darien Chan, Yi-Chan Lee, Ching-Chuan Hsu, Cindy M Chang, Marvin L. Hsieh, Yuan-Yuan Cheng, Yi-Ling Lin, Chien-Hsiun Chen, Ying-Ta Wu, Timothy A Hacker, Joseph C Wu, Timothy Kamp, Patrick C Hsieh
Journal: Circulation Research (2022)

In December 2019, the novel coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) spread around the globe resulting in ~435 million confirmed cases and ~6 million related deaths as of March 2022, according to the World Health Organization. To combat COVID-19 quickly, there have been many attempts to repurpose current FDA-approved drugs or to revive old drugs with anti-viral properties. However, aside from the biological stress imposed by the virus, many of the current treatment options have been known to cause adverse drug reactions. We established a population-based human induced pluripotent stem cell drug screening platform to assess the toxicity of the first line of anti-COVID-19 drugs and to understand viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r=0.86). However, ACE2 expression was undetectable in neurons which correlated with low infection of neurons. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and 4 neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine) which were validated by dose-response curves. These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.
Abstract P1095: Analysis Of Pro-arrhythmic Effects Of The Trisulfated Disaccharide Heparin Fragment, A Potential Antiarrhythmic Drug.
Authors: Enio R Vasques
Journal: Circulation Research (2022)

Background: The heparin fragment called trisulfated disaccharide (TD) acts on the sodium-calcium exchanger by removing excess calcium from cytoplasm with antiarrhythmic action demonstrated in animal models in the reversal of supraventricular and ventricular arrhythmia. However, it is known that drugs with antiarrhythmic potential can induce arrhythmic phenomena, limiting and interrupting the study of new potentially antiarrhythmic drugs. Objective: To evaluate the arrhythmogenic potential of TD in relation to the stimulation of hERG channels in human cardiomyocytes. Material and Methods: Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes in culture were plated onto a fibronectin coated 48 well microelectrode array plate at a density of 25,000 cells per well in iCell® maintenance medium. The plate was incubated for 7 days until a stable beating phenotype was achieved, and the cells were ready for drug treatment. They were dosed with 0.2% DMSO vehicle, E-4031 (0.05μM), or cisapride (0.05μM) as controls (arrhythmogenic drugs). They were also dosed with TD at four concentrations in triplicate. The activity of the cells was recorded prior to dosing and at 1 hour using the Axion Biosystems Maestro MEA system. Beat period (s), fast Na+ slope (V/s), fast Na+ amplitude (mV) and field potential duration (FPD) were evaluated. Results: E-4031 treatment resulted in a significant increase in beat period length (decrease in beat rate) and a decrease in the Na slope and amplitude. There was a very large increase in the FPD. Cisapride showed a very similar response. Both compounds caused an increase in the ratio of the FPD to the beat period length. When the cardiomyocytes were incubated with the different doses of TD, there was a slight increase in the beat period length (decrease in the beat rate), which was observed regarding all the doses. There was an increase in the FPD, which is consistent with the change in beat rates suggesting that the change is purely related to beating and not indicative of any hERG effect or other responses. The ratio of the FPD to the beat period length was the same. There was a slight decrease in the sodium slope and amplitude, but they were not significant. Therefore, the only significant change observed was the beat rate. Conclusion: TD when exposed to human cardiomyocytes did not present an arrhythmogenic potential in relation to the hERG channels, and this is a desirable behavior for an antiarrhythmic drug.
Abstract P3116: Cardioprotective Effects Of Dexrazoxane Derivatives Against Chronic Anthracycline Cardiotoxicity Depend On Topoisomerase II Beta Inhibition And Prevention Of DNA Damage Signaling In The Heart
Authors: Petra Kollarova, Olga Lencova, Galina Karabanovich, Jan Kubes, Nela Vanova, Jaroslav Roh, Tomas Simunek, Petra Sterbova, Martin Sterba
Journal: Circulation Research (2022)

Background: Cardioprotective effects of dexrazoxane (DEX), the only drug approved against anthracycline (ANT) cardiotoxicity, have been traditionally associated with metal chelating properties of its metabolites. However, newer data point to importance of interaction of the parent drug with topoisomerase II beta (TOP2B). Hypothesis: Close derivatives of DEX with different ability to catalytically inhibit TOP2B will show different capability to prevent ANT-induced and TOP2B-depedent DNA damage signaling in the heart which will determine their different cardioprotective effects against chronic ANT cardiotoxicity in vivo . Methods: Chronic ANT cardiotoxicity was induced with daunorubicin (DAU, 3 mg/kg/week for 10 weeks). DEX and its N , N′ -dimethyl derivative were administered at 60 mg/kg, while a water-soluble prodrug of DEX derivative with additional methyl on the aliphatic linker (ICRF-193) was administered at 1 or 5 mg/kg. All drugs were administered 30 min before each DAU dose, and the results were compared with the appropriate control groups. Results: DEX co-treatment almost completely prevented all DAU-induced markers of chronic cardiotoxicity including heart failure-related mortality, left ventricular dysfunction and cardiac troponin T raise in plasma. However, its dimethyl derivative failed to show any cardioprotective potential as all results were not different from the DAU-alone group despite even higher plasma concentrations of the parent compound as well as the main metabolite (compared with DEX). In contrast, the prodrug of ICRF-193 showed dose-dependent cardioprotection with almost complete protection in all studied parameters at 5 mg/kg, despite much lower plasma concentrations of the active derivative ICRF-193. The ability to protect heart against chronic ANT cardiotoxicity correlated with the potency of studied drugs to catalytically inhibit TOP2B in vitro and capability to prevent acute DAU-induced and p53-mediated DNA damage signaling in the heart in vivo . Conclusion: Cardioprotective effects of DEX derivatives against chronic ANT cardiotoxicity in vivo are closely related to their ability to catalytically inhibit TOP2B and prevent ANT-induced DNA damage signaling in the heart.
Abstract GS107: Nil10: A Newly Synthesized Nanoparticle That Reduces Inflammation And Preserves Heart Function In Murine And Porcine Models Of Acute Myocardial Infarction
Authors: Laura Tesoro, Laura Botana, Ignacio Hernandez Navarro, Rafael Ramirez-Carracedo, Jose L Zamorano, Marta Saura, Carlos Zaragoza
Journal: Circulation Research (2022)

Introduction: Interleukin-10 (IL-10) has long been recognized as a key anti-inflammatory cytokine, whose expression is associated to macrophage polarization towards resolution after acute myocardial infarction. Hypothesis: Targeting the IL10 receptor (IL10R) in patients undergoing AMI, may represent a new strategy to improve cardiac function. Methods and Results: We synthesized NIL10, a micelle-based nanoparticle conjugated to an IL-10 agonist, to analyze the effect on cardiac function and inflammation resolution after cardiac ischemia/reperfusion. After confirmation of NIL10 (conjugated with Rhodamine) co-localization to IL-10R, as detected by immunohistofluorescence (Fig. 1A), intravenous administration of 1 mg/kg NIL10 in mice and pigs subjected to AMI, efficiently decreased left ventricle fibrosis and significantly improved left ventricle ejection fraction (LVEF), by day 7 after injection, when compared to animals injected with, NIL10SC, a nanoparticle control (Fig. 1B-C). As expected, NIL10 induced macrophage polarization towards M2-like macrophages after day 3 of reperfusion (Fig D), by at least promoting IL-10R activity, as shown by increased phosphorylation of IL-10R and the downstream STAT3 in the necrotic area of the heart (Figure 1E). STAT3-dependent inflammation inhibition was assayed by administration of 50μM NIL10 in RAW-247 cells stimulated with 500 μM LPS, in which nuclear translocation of NF-κB was significantly reduced (Fig. 1E) by at least phosphorylation of I-κB-α. Conclusions: Our findings show NIL10 as a new tool to improve cardiac function in hearts under AMI, at least through inhibition of STAT3-induced nuclear translocation of NF-κB.
Abstract P2116: Hyperglycemia Mediated Changes In A Human Cardiomyocyte Cell Model
Authors: Binata Joddar, Irtisha Singh, Munmun Chattopadhyay, Vikram Thakur
Journal: Circulation Research (2022)

Introduction: Hyperglycemia-mediated cardiac dysfunction is a critical initiator in the development of vascular complications, which, in turn, leads to cardiac fibrosis. In this study, we investigated the role of the Hippo signaling pathway in cardiomyocytes to study the complex signaling network of YAP1/TAZ on fibrotic and vascular inflammatory mediators in hyperglycemic condition. This in-vitro study demonstrated that YAP1/TAZ signaling is highly activated in the hyperglycemic cardiomyocytes. To further investigate the differentially expressed genes that are related to inflammation and fibrosis, RNA-sequencing studies were employed. Methods: To investigate the effects of hyperglycemia-mediated changes in cardiomyocytes, we used human AC16 cells cultured in-vitro under normoglycemic (5 mM D-Glucose) and hyperglycemic (50 mM D-glucose) conditions. After 24-hours of hyperglycemic insult, cells were collected and processed for RNA-seq studies. Furthermore, we also performed Western Blot analysis to evaluate the protein expression of YAP1/TAZ under hyperglycemia induced stress conditions. Results: Our study showed a significant upregulation of the protein expression of the YAP1/TAZ pathway in hyperglycemic cardiomyocytes. RNA-seq studies revealed differentially expressed genes (DEG) in the hyperglycemic condition in comparison with the normoglycemic condition. Among the extracellular matrix proteins, the following ECM and related markers were significantly upregulated including MMP3, TNC, TGF-beta1 and 2, COL4A1, FN1 and FGF-2. Altered expression of inflammatory mediators included the following markers, IL-6, CXCL10, CXCL12, CCL2 and VEGF-C. In addition, the following transcriptional co-activators were also significantly upregulated, including EPHA2 and MYOCD. Conclusions: This study suggests that changes in YAP1/TAZ signaling increases vascular inflammation in response to hyperglycemia. This also leads to increased expression of inflammatory mediators as shown by our results. Thus, the inhibition of the YAP1/TAZ pathway may prevent and improve hyperglycemia associated vascular damage and inflammation.
Abstract P3092: Transcriptomic Landscape Of The Postnatal Atrioventricular Conduction System
Authors: Yena Oh, David Cook, Jin G. Park, Barbara Vanderhyden, Nikhil Munshi, Kyoung-Han Kim
Journal: Circulation Research (2022)

The atrioventricular conduction system (AVCS) is a network of specialized cardiomyocytes responsible for coordinated spreading of electrical impulses throughout the heart to allow synchronized contractions. Specifically, it is composed of the AV node (AVN), which delays the electrical signal, and the ventricular conduction system (VCS) (i.e. His bundle, bundle branches and Purkinje fibers), which rapidly propagates the signal throughout the ventricles. Although these AVCS structures were discovered &gt;100 years ago, its molecular constituents are not fully known. In this study, AVCS cells, making up ~0.05% of myocytes (~500 cells/heart), were isolated from early postnatal hearts (Postnatal day 1 to 4) of fluorescent reporter mice (Cntn2- Cre;Rosa26TdTomato), purified using fluorescence-activated cell sorting, and were subjected to single-cell RNA-sequencing. Unbiased cluster analysis on ~7000 AVCS cells demonstrated distinct transcriptomic profiles in the AVN, proximal-VCS (i.e. His bundle and bundle branches) and distal-VCS (i.e. Purkinje fibers). Conforming to previous studies, global conduction markers, such as Etv1 and Kcne1, were present throughout the entire AVCS, whereas a VCS-specific TF, Irx3 , was expressed only in the VCS. Additionally, Tbx3, Pcp4, Nppa and Lyz2 were enriched in the proximal, not distal, VCS. Sub-clustering analysis of AVN and proximal-VCS further identified unique molecular profiles, such as Shox2 (in compact AVN) and Rspo3 (likely in lower nodal region connecting AVN and proximal-VCS). Moreover, we uncovered a potential regulatory relationship between Irx3 and Tbx3 in the AVCS, mediating their downstream targets, Gja5 and Gja1 . In Irx3 and Tbx3 -positive proximal-VCS, Gja5 and Gja1 expressions were lower compared to only Irx3 -positive distal-VCS, whereas in only Tbx3 -positive AVN, both Gja5 and Gja1 expressions were undetected. Importantly, this regional difference was recapitulated in cultured neonatal mouse atrial and ventricular myocytes overexpressing Irx3 and/or Tbx3 . Overall, our study provides a comprehensive view of the cellular and molecular heterogeneity within the postnatal AVCS at a high-resolution and reveals novel gene regulatory mechanisms that may govern the development of the AVCS.
Abstract P1136: Amino Acid Availability Regulates Differentiation Of HIPSC-derived Cardiomyocytes In A Protein-free System
Authors: Davi M Lyra Leite, Raymond R Copley, Phillip P Freeman, Donald E McKenna, Katherine A Fetterman, Disheet A Shah, Ali Negahi Shirazi, Hananeh Fonoudi, Tarek M Mohamed, Malorie Blancard, Paul W Burridge
Journal: Circulation Research (2022)

Traditional protocols for the differentiation of hiPSC-derived cardiomyocytes (hiPSC-CMs) rely on complex media and the use of animal or recombinant proteins either directly or in supplements, such as B27, to obtain tissue monolayers. This fact decreases their reproducibility, while potentially increasing their costs and limiting higher-throughput production of cardiomyocytes for applications in both regenerative medicine, disease modeling, and pharmacological screenings. Albumin/serum-free protocols have been developed but produce cells with limited functionality and at lower yields, despite them being TNNT2-positive. We previously demonstrated it is possible to simplify the differentiation protocol utilizing a stepwise approach and combining time-point interventions with small molecules or nutritional inputs. Here, we performed a thorough screening of commercial media and their suitability for differentiation of hiPSC-CMs. We identified suitable basal media formulations and developed a novel protein-free differentiation protocol (PFDM) for generating hiPSC-CMs that preserves purity, yield, morphology, and functionality while reducing the cost of the differentiation process. PFDM also enabled the identification of nutritional requirements essential for cardiac differentiation and allowed a detailed investigation into how some common components supplemented during hiPSC-CM differentiation impact tissue morphology and contractility. We showed that non-essential amino acids regulate differentiation in a time-dependent manner. Similarly, antioxidant agents such as sodium pyruvate and ascorbic acid, while essential for differentiation, are potentially harmful during early cardiac mesoderm induction. Lastly, we validated this PFDM methodology in 35 control and patient-derived hiPSC lines, with monolayer differentiations in 6- and 12-well plates, 15 cm dishes, in addition to differentiations in 3D using 100- and 250-mL spinner flasks.
Airway mucus
Authors: JG Widdicombe
Journal: European Respiratory Journal (1989)

Airway surface liquid (ASL), a mixture of periciliary fluid and submucosal gland secretions, was collected from the ferret isolated trachea in vitro. The trachea was closed, without possibility of evaporation. The collected ASL was hyperosmolar (310-350 mosmol.kg-1) compared with Krebs-Henseleit solution (280 mosmol.kg-1). Compared with surrounding Krebs-Henseleit solution, the ASL had higher sodium and chloride contents, and considerably higher potassium and calcium contents. The ASL was acid (pH about 7.00) compared with Krebs-Henseleit solution (pH 7.40). Applying methacholine and salbutamol to the preparation significantly changed most of the electrolyte concentrations, and reduced pH. The pH was not significantly changed by bubbling the surrounding buffer with 0-20% CO2, with corresponding buffer changes in pH of 6.95-8.05. Adding labelled albumin to the external buffer resulted in lumenal concentrations that, in the presence of salbutamol, were higher than outside. This and other evidence suggested that albumin could be actively secreted into the lumen, a process enhanced by salbutamol. Thus ASL is hyperosmolar, of different electrolyte composition from interstitial fluid, and of low pH which is homeostatically regulated. The epithelium can actively secrete albumin into the lumen.